NEUROENDOCRINE AND BEHAVIORAL ACTIONS OF CORTICOTROPIN R

该项目的总体目标是更好地了解促肾上腺皮质激素释放激素(CRH)和其他类似CRH的分子如何使哺乳动物成功地应对压力。将研究小鼠模型，以利用我们和其他人创造的基因敲除和替换方法。主要涉及3个方面：1.应激时内分泌反应的激活；2.应激时行为反应的激活；3.食欲和生殖应激时的抑制。具体地说：1.糖皮质激素是生命所必需的吗？肾上腺功能不全会导致死亡，而CRH缺陷小鼠尽管糖皮质激素水平极低(但可检测到)，但仍有正常寿命。我们将确定，面对完全性糖皮质激素缺乏时，CRH缺乏可预防死亡。如果是这样的话，这将表明糖皮质激素对哺乳动物的生存并不是必不可少的。昼夜节律在ACTH中的作用是什么？我们将验证这一假设，即正常小鼠血液中ACTH的每日上升通过防止肾上腺皮质细胞凋亡来维持基础肾上腺的完整性。CRH和加压素(VP)在应激诱导的和昼夜节律激活的垂体肾上腺轴中的相对作用是什么？我们将研究CRH、VP或CRH和VP基因同时缺失的小鼠，分析它们对急性和慢性应激源以及昼夜节律线索的下丘脑、垂体和肾上腺的反应。2.在CRH基因敲除小鼠中，介导恐惧反应的CRH受体1配体的身份是什么？是尿皮质素，还是一种新的哺乳动物CRH样多肽？3.在应激反应中，CRH及其相关分子在抑制食欲和生殖方面起什么作用？

The overall goal of this project is to better understand how corticotropin-releasing hormone (CRH) and other CRH-like molecules allow mammals to respond successfully to stress. Mouse models will be studied to take advantage of gene knockout and replacement methods that we and others have created. 3 broad areas will be addressed: 1. The activation during stress of endocrine responses; 2. The activation during stress of behavioral responses; and 3. The suppression during stress of appetite and reproduction. Specifically: 1. Are glucocorticoids necessary for life? Adrenal insufficiency causes death, whereas CRH-deficient mice have a normal lifespan despite extremely low (but detectable) levels of glucocorticoid. We will determine it CRH deficiency prevents death in the face of complete glucocorticoid deficiency. If so, this will show that glucocorticoids are not essential for mammalian survival. What is the function of the circadian rhythm in ACTH? We will test the hypothesis that the daily rise in blood ACTH in normal mice functions to maintain basal adrenal integrity by preventing adrenocortical apoptosis. What are the relative roles of CRH and vasopressin (VP) in the stress-induced and circadian activation of the pituitary adrenal axis? We will study mice with deletions in the CRH, VP or both CRH and VP genes, which will be analyzed for their hypothalamic, pituitary and adrenal responses to acute and chronic stressors, as well as to circadian cues. 2. What is the identity of the CRH receptor 1 ligand that mediates fear responses in CRH knockout mice? Is it urocortin, or a new, mammalian CRH-like peptide? 3. What is the role of CRH and related molecules in the suppression of appetite and reproduction during the stress response?